This invention relates to the cellularization and/or recellularization of a tissue substrate or a synthetic substrate to form a synthetic tissue, which can be used in a prosthesis. More particularly, the invention relates to association of bioactive molecules with a substrate, the bioactive molecules being effective at attracting precursor cells capable of differentiating and/or transdifferentiating into fibroblasts/myofibroblasts or endothelial cells.
Prostheses, i.e., prosthetic devices, are used to repair or replace damaged or diseased organs, tissues and other structures in humans and animals. Prostheses must be generally biocompatible since they are typically implanted for extended periods of time. For example, prostheses can include artificial hearts, prosthetic heart valves, ligament repair material, vessel repair, surgical patches constructed of mammalian tissue and the like.
Prostheses can be constructed from natural materials such as tissue, synthetic materials or a combination thereof. For example, prostheses such as mechanical heart valves are manufactured from biocompatible metals, as well as other materials like graphite and polyester. Although mechanical heart valves have the advantage of proven durability through decades of use, they are associated with a high incidence of blood clotting on or around the valve. Blood clotting can lead to acute or subacute closure of the valve or the associated blood vessel. For this reason, patients with implanted mechanical heart valves remain on anticoagulants for as long as the valve remains implanted. Anticoagulants impart a 3-5% annual risk of significant bleeding and cannot be taken safely by certain individuals.
Besides mechanical heart valves, heart valve bioprostheses can be constructed from tissue components with tissue leaflets or polymer leaflets. Prosthetic tissue heart valves can be derived from porcine heart valves or manufactured from other biological material such as bovine pericardium. Biological materials in prosthetic heart valves generally have profiles and surface characteristics that provide laminar, nonturbulent blood flow. Therefore, intravascular clotting is less likely to occur than with mechanical heart valves. Unfortunately, prosthetic tissue heart valves are limited by a tendency to fail beginning about seven years following implantation. Valve degeneration is particularly rapid in young patients and during pregnancy.
Calcification, i.e., the deposition of calcium salts, especially calcium phosphate (hydroxyapatite), appears to be a major cause of degeneration in bioprostheses. Calcification of heart valve prostheses having tissue leaflets or polymer leaflets can lead to failure. Efforts to address the calcification problem have included treating glutaraldehyde-fixed valve prostheses with compounds to reduce calcium nucleation. Other approaches include use of alternative tissue fixation techniques since evidence suggests that glutaraldehyde fixation can contribute to calcification and mechanical degradation. In addition, since nonviable cells can be sites for calcium deposition, various processes have been developed to remove nonviable cells while leaving the extracellular matrix intact. Intact tissue with viable cells has natural protection against calcification.
Another major disadvantage of tissue and polymer based prostheses is their inability to regenerate. Long term durability is affected by the ability of viable cells to populate the implanted substrate and to carry out maintenance functions. The importance of viable cells has been studied in the context of homograft transplants, i.e., transplants from one member of a species to another member of the same species. Proper homograft preservation can maximize the number of viable cells remaining in the tissue as determined by matrix protein synthesis. Preservation techniques that do not promote cell survival, such as long term storage at 4xc2x0 C., are associated with reduced in vivo durability and increased reoperation rates.
The extracellular matrix is maintained by collagen secreting cells called fibroblasts. Fibroblasts are differentiated cells with a well defined morphology. They are capable of a variety of different functions depending on their association with a specific tissue. Myofibroblasts are fibroblasts that express relatively more contractile proteins such as myosin and actin. In situ, Fibroblasts reside below the endothelial monolayer that covers the surface of vascular tissue.
In a first aspect, the invention pertains to a prosthesis including a substrate with an associated attraction compound. The attraction compound binds viable fibroblast precursor cells with the substrate.
In another aspect, the invention pertains to a method of producing a prosthesis, the method comprising forming the prosthesis at least partially from a substrate with an associated attraction compound that attracts viable fibroblast precursor cells.
Moreover, the invention pertains to a kit comprising a container and instructions for the modification of a prosthesis with the attraction compound, the container holding an attraction compound, the attraction compound binding viable fibroblast precursor cells with the substrate.
In a further aspect, the invention pertains to a method for distributing a medical article for use by health care professionals, the method comprising placing a prosthesis into a package under sterile conditions and distributing the package for use by health care professionals, the prosthesis formed at least partly from a substrate with an associated attraction compound that bind viable fibroblast precursor cells.
In an additional aspect, the invention pertains to a prosthesis comprising a substrate with an associated attraction compound, the attraction compound binding viable endothelial cell precursor cells.
Furthermore, the invention pertains to a kit comprising a container and instructions for the modification of a prosthesis with the attraction compound, the container holding an attraction compound, the attraction compound binding viable endothelial cell precursor cells.